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Page 2 of 29 Aguiar. Rare Dis Orphan Drugs J 2024;3:13 https://dx.doi.org/10.20517/rdodj.2023.56

INTRODUCTION
Biological markers or biomarkers are defined, according to the National Institutes of Health Biomarkers
Definitions Working Group, as “a characteristic that is objectively measured and evaluated as an indicator
of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic
[1]
intervention” . Biomarkers may have great value in several clinical applications, including their use as
diagnostic tools, for staging or classifying the extent of the disease, disease progression and prognosis,
predicting and monitoring clinical response to an intervention, and facilitating early evaluation of efficacy
[1]
and safety in clinical trials . However, rigorous validation of the relationship between a proposed
biomarker, disease activity, and outcome is of key importance .
[2]
Candidate biomarkers for lysosomal storage disorders (LSDs) are mainly analytes and imaging techniques.
Analytes may range from simple metabolites to complex proteins and, for LSDs, can be divided into two
categories: molecules that accumulate in tissues and body fluids directly due to the enzymatic defect, and
molecules produced by the cells in response to lysosomal storage .
[3]

One of the most urgent needs in Anderson-Fabry disease (FD) is for reliable and validated biomarkers,
ideally measured by non-invasive testing. This urgency is mainly related to the characteristics of and pitfalls
in FD: diagnosis, determination of phenotype (classical vs. late-onset), evaluation of preclinical involvement,
monitoring and assessment of treatment response.

The diagnosis of FD is based mainly on the enzymatic activity of α-galactosidase A and GLA gene
sequencing, but both methods have limitations that need to be addressed. Due to random X chromosome
inactivation, female patients may present significant residual enzymatic activity and about one-third may
have α-galactosidase A activity within the normal range for the general population; thus, the diagnosis can
only be reliably performed by GLA sequencing . Moreover, in male patients with residual enzymatic
[4]
activity (> 5% of normal) definitive diagnosis of FD may only be confirmed by GLA gene mutation
[5,6]
analysis . However, GLA gene sequencing may not provide a definitive diagnosis for several reasons: most
[7]
GLA mutations found in FD patients are novel/“private”, there are various mutations of unknown
[7,8]
significance, and routine sequencing can only identify a mutation in 97% of male patients with FD .
Hence, reliable biomarkers may help diagnosis in these situations .
[1]
Furthermore, FD is clinically heterogeneous (in presentation and rate of progression) [9-12] , with genetic
factors and gender certainly contributing to this fact [13,14] . However, the clinical picture may vary widely even
in patients within the same family or with the same mutation, and thus other genetic, epigenetic, and
environmental factors also contribute to clinical heterogeneity. Therefore, the identification of prognosis
biomarkers and biomarkers capable of determining the likely phenotype (classical vs. late-onset) is
[1]
paramount to the identification of patients at increased risk of a progressive disorder .
FD is clinically silent for a long period; per example, severe storage material inclusions in podocytes and
distal tubules, as well as segmental foot process effacement and nonspecific degenerative lesions, have been
identified even at early stages of Fabry nephropathy, in pediatric and adult patients with minimal or no
alterations in standard renal tests (namely glomerular filtration rate, albuminuria or proteinuria) [15-20] .
Although the optimal timing of disease-specific treatment (DST) beginning is not known, increasing
evidence suggests that an early treatment strategy may be more effective in preventing cardiac and renal
manifestations and major clinical events. However, currently, the European recommendations for DST
initiation are based on functional or structural manifestations . Nonetheless, as mentioned above, there is
[21]
a long clinically silent period before overt major organ manifestations, characterized by histological changes